Towards NO‐free Regulation of sGC: Design and Synthesis of trans‐AB‐porphyrins. Issue 2 (5th June 2015)

• Record Type: Journal Article
• Authors: Smoleń, Sabina; Walaszek, Dominika J.; Karczewski, Maksymilian; Martin, Emil; Gryko, Dorota
• Is Part Of: Israel journal of chemistry. Volume 56:Issue 2/3(2016)
• Page Start: 156
• Page End: 168
• Publication Date: 2015-06-05
• Subjects: [2+2]‐dipyrromethane condensation -- amino acids -- enzymes -- soluble guanylate cyclase -- trans‐AB‐porphyrins; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/ijch.201500019
• Languages: English
• ISSNs: 0021-2148

Abstract

Abstract: The pathogenesis of the cardiovascular system is often associated with dysfunction of soluble guanylate cyclase (sGC), which can be stimulated in both an NO‐dependent and ‐independent manner. It was previously reported that PPIX and its amphiphilic derivatives markedly activate the enzyme. To date, all porphyrins studied are naturally occurring compounds or their derivatives, possessing substituents at β‐positions. Such porphyrins are of limited abundance and their derivatives or analogues are difficult to synthesize, while synthetic meso ‐substituted porphyrins are easy to prepare. Thus, we have decided to study their effect on guanylate cyclase. To this end, a series of trans ‐AB‐porphyrins, bearing both hydrophilic and hydrophobic groups at the opposite ends of the macrocycle, loosely mimicking the arrangement of the substituents in PPIX, was design and synthesized. Their synthesis involves preparation of suitable building blocks – dipyrromethanes, starting from aldehydes or acetals and following an acid‐catalyzed [2+2]‐dipyrromethane condensation. Biological properties of synthesized porphyrins with regard to sGC activation were tested. meso ‐Substituted porphyrins do interact with sGC, though they are poor activators, indicating that further optimization of their structure is required. Abstract :